Methods of Using Inhaled Nitric Oxide Gas for Treatment of Acute Respiratory Distress Syndrome in Children

ABSTRACT

The present invention provides a treatment of acute respiratory distress syndrome (ARDS) in children using dosing of nitric oxide at low concentrations, such as less than 10 ppm.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. §120 of U.S. patentapplication Ser. No. 14/593,085, filed Jan. 9, 2015, which claims thebenefit under 35 U.S.C. §119(e) to U.S. Provisional Application No.61/925,925, filed Jan. 10, 2014, the entire contents of which areincorporated herein by reference in their entirety.

FIELD

The present invention relates to methods of using inhaled nitric oxidegas to treat and/or prevent acute respiratory distress syndrome inchildren.

BACKGROUND

Acute respiratory distress syndrome (ARDS), previously known as adultrespiratory distress syndrome, is a life-threatening lung condition thatprevents enough oxygen from getting to the lungs and into the blood.ARDS may result from an injury to or an infection in the lungs of apatient.

Inhaled nitric oxide (iNO) transiently improves oxygenation in adultswith ARDS, but does not significantly decrease mortality. The impact ofiNO on outcomes in children with ARDS has not been previously evaluatedin a randomized, non-crossover trial.

SUMMARY

One or more embodiments of the present invention are directed to amethod for treating a child with ARDS or preventing ARDS in a child atrisk of developing ARDS via administration of a low dose of inhalednitric oxide (iNO). In one or more embodiments, the dose of iNO is lessthan about 10 ppm, such as in the range from about 0.1 ppm to about 8ppm or in the range from dose in the range from about 2 ppm to about 6ppm. In some embodiments, the NO dose is less than about 8 ppm. In oneor more embodiments, the NO dose is about 5 ppm.

The iNO may be administered for a relatively short-term treatment, suchas for a treatment period of up to 28 days. In exemplary embodiments,the NO is administered for a treatment period in the range from 2 daysto 2 months.

The iNO may be administered during patient inspiration, expiration, orportions thereof. In one or more embodiments, the iNO is administeredduring only a portion of inspiration, such as only administering iNOduring the first half of inspiration.

According to one or more embodiments, the child may be less than 16years old. Exemplary ages for the child include those in the range from44 weeks post-conceptional age to 16 years of age.

In one or more embodiments, the child is not subjected to extracorporealmembrane oxygenation during NO administration.

In one or more embodiments, NO increases the number of days that thechild is alive and ventilator-free at 28 days after the start of NOadministration.

Also provided is a method of increasing extracorporeal membraneoxygenation-free (ECMO-free) survival in children with ARDS or at riskof developing ARDS, the method comprising administering a gas comprisingNO to a child in need thereof at a dose of less than 10 ppm NO. In oneor more embodiments, the NO dose may be the in range from about 0.1 ppmto about 8 ppm, such as about 5 ppm.

Also provided is a method of increasing the number of ventilator-freedays in children with ARDS or at risk of developing ARDS, the methodcomprising administering a gas comprising nitric oxide (NO) to a childin need thereof at a dose of less than 10 ppm NO. In one or moreembodiments, the NO dose may be the in range from about 0.1 ppm to about8 ppm, such as about 5 ppm.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the final disposition of all subjects in a studyinvestigating the administration of 5 ppm iNO versus placebo for adultswith ARDS.

FIG. 2 shows a summary of the patient population in a studyinvestigating the administration of 5 ppm iNO versus placebo forchildren with AHRF according to one or more exemplary embodiments of theinvention.

FIG. 3 shows the ventilation settings and gas exchange at enrollment forthe AHRF in children study.

FIG. 4 shows a summary of the patient randomization and disposition forthe AHRF in children study.

FIG. 5 shows the oxygenation index at baseline, 4 hours, 12 hours and 24hours for the AHRF in children study.

FIG. 6 shows a summary of the results for the AHRF in children study.

DETAILED DESCRIPTION

The present invention is directed to the unexpected finding that shortterm treatment of ARDS in children using inhaled nitric oxide (iNO) gasresulted in an increased number of days that a child is ventilator-freeat 28 days after the start of iNO therapy. It was also unexpectedlyfound that the rate of extracorporeal membrane oxygenationoxygenation-free (ECMO-free) survival is significantly higher inchildren treated with iNO therapy than children administered a placebo.As previous studies investigating the use of iNO for treating ARDS inadults did not meet their primary endpoints of reduced mortality orincrease in days alive and off assisted breathing, it was surprisingthat a clinical study investigating iNO therapy for children with ARDSapproached statistical significance for the number of days patientremains alive and extubated to day 28 after initiating study therapy.

Accordingly, one or more embodiments of the present invention providefor the treatment and/or prevention of pediatric ARDS using iNO.

DEFINITIONS

As used herein the following terms shall have the definitions set forthbelow.

As used herein, the term “therapeutic composition” refers to a drugdelivered to a patient. The use of the term “therapeutic composition” isin concurrence with the Food and Drug Administration's (FDA) definitionof a drug: articles intended for use in the diagnosis, cure, mitigation,treatment, or prevention of disease. Such drugs may include gasescomprising nitric oxide, such as nitric oxide in a diluent or carriergas such as nitrogen or helium. The NO-containing gas may be provided byany known method, such as from a gas cylinder or chemically generatingthe NO at or near the place of administration. The NO-containing gas maybe at a higher concentration in the cylinder or other gas source and bediluted to a delivery concentration prior to use. The drug may beprovided by a drug delivery device.

The device designation as defined herein is in concurrence with the Foodand Drug Administration's (FDA) definition of a device: A device isdefined as an instrument, apparatus, implement, machine, contrivance,implant, in vitro reagent, or other similar or related article,including a component part, or accessory which is:

-   -   recognized in the official National Formulary, or the United        States Pharmacopoeia, or any supplement to them,    -   intended for use in the diagnosis of disease or other        conditions, or in the cure, mitigation, treatment, or prevention        of disease, in man or other animals, or    -   intended to affect the structure or any function of the body of        man or other animals, and which does not achieve any of its        primary intended purposes through chemical action within or on        the body of man or other animals and which is not dependent upon        being metabolized for the achievement of any of its primary        intended purposes.

As described herein, the device may be a nitric oxide delivery devicethat administers a gas comprising nitric oxide. Suitable nitric oxidedelivery devices include the INOvent®, INOmax® DS and INOmax DSIR®delivery devices, available from Ikaria Inc. in Hampton, N.J.

As used herein, the term “treating” refers to the treatment of a diseaseor condition of interest in a patient (e.g., a mammal) having thedisease or condition of interest, and includes, for example one or moreof the following:

-   -   (i) preventing the disease or condition from occurring in a        mammal, in particular, when such mammal is predisposed to the        condition but has not yet been diagnosed as having it;    -   (ii) inhibiting the disease or condition (i.e., arresting its        development);    -   (iii) reducing the extent of disease or condition (i.e., causing        regression of the disease or condition); or    -   (iv) ameliorating the symptoms resulting from the disease or        condition (i.e., relieving pain without addressing the        underlying disease or condition).

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

As used herein, “short term treatment” refers to treatment periods up toabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 25 days or one month, twomonths or three months. The treatments described herein may have acertain minimum and/or maximum treatment periods. Minimum treatmentperiods may include about 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 15, 18 or24 hours or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20,25, 28 or 30 days. Maximum treatment periods may include about 12, 18 or24 hours or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20,25, 28 or 30 days or about 2, 4, 6, 8, 10 or 12 weeks or about 1, 2, 3,4, 5 or 6 months.

As used herein, “chronic treatment” refers to treatment periods ofgreater than three months.

As used herein, the term “patient” refers to a human to whom treatmentaccording to the methods of the present invention is provided.

As used herein, the term “subject” is used interchangeably with“patient”.

As used herein, the term “child” refers to a human that is under 18years of age. In one or more embodiments, the child to be treated may bebetween the ages of 44 weeks post-conceptional age to 16 years of age.“Post-conceptional age” refers to the age of an infant relative to thedate of conception plus the chronological age. In various embodiments,the lower age range for the child may be 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49 or 50 weeks post-conceptional age or 1, 2, 3, 4,5, 6, 7 or 8 weeks chronological age or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 15, 18, 21 or 24 months chronological age. The term“chronological age” refers to the age relative to the date of birth. Invarious embodiments, the upper age range for the child may be 18, 17,16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 years of age.

As used herein, the term “administering” refers to any mode oftransferring, delivering, introducing or transporting the therapeuticcomposition, device or other agent to a subject. Administration of thetherapeutic composition, device or other agent may be conductedconcurrently or sequentially in time. Additionally, administration ofthe therapeutic composition, device and other agent(s) may be via thesame or different route(s).

As used herein, the term “effective amount” refers to that amount ofwhich, when administered to a patient (e.g., a mammal) for a period oftime is sufficient to cause an intended effect or physiological outcome.The amount of therapeutic composition which constitutes an “effectiveamount” will vary depending on the condition and its severity, themanner of administration, and the patient (e.g., the age of the mammalto be treated), but can be determined routinely by one of ordinary skillin the art having regard to his own knowledge and to this disclosure.

For example, in one embodiment, the term “effective amount” refers tothe amount that can achieve a measurable result. In one embodiment, an“effective amount” is, for example, an amount that when administered toa human subject in need of medical treatment in a controlled Phase 2 orPhase 3 clinical trial produces a statistically significant benefit on apredefined clinical endpoint.

As used herein, the term “indications” includes, but is not limited to,pulmonary disease, acute lung injury (ALI), acute respiratory distresssyndrome (ARDS) and acute hypoxemic respiratory failure (AHRF). ARDS isrelated to the medical condition AHRF, and ARDS often has aperfusion-related component such as pulmonary hypertension (PH).

ARDS and ALI may be determined by any acceptable criteria by one ofordinary skill in the art. On such set of criteria include (1) acutebilateral infiltrates on chest radiographic appearance, (2) the ratio ofthe partial pressure of oxygen in arterial blood to the fraction ofinspired oxygen (PaO₂/FiO₂ or PF ratio) of less than 200 for ARDS andless than 300 for acute lung injury (ALI), and (3) noncardiogenicpulmonary edema based on an assessment of the left atrial fillingpressure by means of a wedged pulmonary artery catheterization orclinical assessment. Typically in children, chest radiographs orechocardiograms are substituted for pulmonary artery catheterization toassess left atrial filling pressures, especially given the relativelylow incidence of cardiogenic pulmonary edema in children. The acceptedmedical criteria used to determine any of the diseases or disordersdescribed herein may adjust due to developments in the medical communityor advances in technology

The methods and compositions of the present invention may be used totreat or prevent a variety of diseases and disorders, including anydisease or disorder that has been treated using any of a gaseous form ofnitric oxide, a liquid nitric oxide composition or any medicallyapplicable useful form of nitric oxide, including any described in U.S.Pat. No. 6,103,275.

As used herein, the term “tissue” refers to any mammalian body tissue,desirably a human body tissue, including damaged tissue. A body tissue,according to the teachings to the present invention, may be, but is notlimited to, muscle tissue, particularly cardiac tissue and, moreparticularly, myocardial tissue, such as left ventricular wallmyocardial tissue.

As used herein, the term “damaged tissue” refers to any damagedmammalian body tissue, including, for example, damaged pulmonary tissue,and particularly, damaged lung tissue.

Gases and Detection of Gases

Methods for safe and effective administration of NO by inhalation arewell known in the art. See, e.g., Zapol, U.S. Pat. No. 5,570,683; Zapolet al., U.S. Pat. No. 5,904,938; Bathe et al., U.S. Pat. No. 5,558,083;Frostell et al., 1991, Circulation 83:2038-2047. NO for inhalation isavailable commercially (INOmax®, Ikaria, Inc., Hampton, N.J.). Each ofthese references is incorporated by reference in its entirety. In thepresent invention, NO inhalation preferably is in accordance withestablished medical practice.

iNO is commercially available as INOmax® for the treatment of hypoxicrespiratory failure in term and near-term neonates. See, e.g., INOmax®,package insert (www.inomax.com), which is incorporated by reference inits entirety.

Inhaled nitric oxide may be formulated for use by dilution in nitrogenand/or other inert gases and may be administered in admixture withoxygen, air, and/or any other appropriate gas or combination of multiplegases at a desired ratio.

In one or more embodiments, the NO is administered at a dose less than10 ppm. Exemplary dose ranges include minimum doses of about 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5,5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9 or 9.5 ppm and maximum doses of about 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 11,12, 13, 14, 15, 20, 25, 30, 35, 40, 45 or 50 ppm.

The nitric oxide may be administered during the patient's entireinspiration, or may be administered for only a portion of the patient'sinspiration. In one or more embodiments, the NO is not administered inthe last about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85% or 90% of inspiration (i.e. the NO isadministered only at the beginning of the patient's inspiration). NOadministration can start and end at any point during inspiration andexpiration.

In one or more embodiments, the nitric oxide therapy is begun early onin the treatment of ARDS and/or prevention of ARDS. It is believed thatadministering nitric oxide as described herein may have a greaterbenefit if the nitric oxide is administered before ARDS develops orearly in the development of ARDS.

In some embodiments, iNO administration may be used as an alternative toextracorporeal membrane oxygenation (ECMO) therapy for children withARDS. A patient's respiratory and/or pulmonary parameters may be checkedfrequently to determine if ECMO therapy is necessary. For example, thepatient's parameters may be checked multiple times per days (such as 2,3, 4, etc. times per day) or may be checked daily or every few days(such as every 2, 3, 4, etc. days). iNO may also be administered inaddition to ECMO therapy.

EXAMPLES Comparative Example 1 Adults ARDS Study Introduction

Inhaled nitric oxide (iNO) is a vasodilator indicated for treatment ofterm and near-term neonates with hypoxic respiratory failure associatedwith clinical or echocardiographic evidence of pulmonary hypertension.In these patients, iNO has been shown to improve oxygenation and reducethe need for extracorporeal membrane oxygenation therapy. NO binds toand activates cytosolic guanylate cyclase, thereby increasingintracellular levels of cyclic guanosine 3′,5′-monophosphate (cGMP).This, in turn, relaxes vascular smooth muscle, leading tovasodilatation. Inhaled NO selectively dilates the pulmonaryvasculature, with minimal systemic vasculature effect as a result ofefficient hemoglobin scavenging. In acute lung injury (ALI) and acuterespiratory distress syndrome (ARDS), increases in partial pressure ofarterial oxygen (PaO₂) are believed to occur secondary to pulmonaryvessel dilation in better-ventilated lung regions. As a result,pulmonary blood flow is redistributed away from lung regions with lowventilation/perfusion ratios toward regions with normal ratios.

Many pharmacologic treatments have been investigated in ARDS patients,including alprostadil, acetylcysteine, corticosteroids, surfactant,dazoxiben, and acyclovir. A meta-analysis of trials completed through2004 indicated no statistically significant mortality benefit with anyof the above-mentioned treatments.

Study

A large-scale, randomized, blinded, placebo-controlled study was carriedout in the Intensive Care Units (ICUs) of 46 US hospitals to evaluatethe efficacy of low-dose (5 ppm) iNO in 385 patients with moderatelysevere Acute Lung Injury (ALI). The primary endpoint of this study wasnumber of days alive and off assisted breathing. Results of anintent-to-treat analysis revealed that inhaled NO (iNO) had nosignificant benefit versus control (nitrogen gas) as it related tomortality, days alive and off assisted breathing, or days alive andmeeting oxygenation criteria for extubation. However, iNO treatment didresult in a significant increase (p<0.05) in partial pressure ofarterial oxygen (PaO₂) during the initial 24 hours of treatment thatresolved by 48 hours.

Safety Results

Safety results for the initial 28-day study period have been reportedand are summarized briefly here. A total of 630 adverse events (AEs)were reported for patients treated with iNO versus 666 events for thosewho received placebo. Respiratory system AEs occurred in 51% versus 61%of patients receiving iNO and placebo, respectively, primarily due tohigher frequencies of pneumonia, pneumothorax, and apnea in the placebogroup. Frequency of other AEs was similar in both groups.

Patients

Patients had acute lung injury (ALI), defined by a modification ofAmerican-European Consensus Conference criteria (PaO₂/inspired oxygenconcentration [FiO₂] ratio of ≦250 mm Hg), due to causes other thansevere sepsis. Patients with evidence of non-pulmonary system failure atthe time of randomization and sepsis-induced ARDS were excluded.Patients were also excluded if they had sustained hypotension requiringvasopressor support, hemodynamic profiles supporting severe sepsis,severe head injury, severe burns, or evidence of other significant organsystem dysfunction at baseline.

Treatment

Patients were randomly assigned to receive either inhaled placebo gas(nitrogen) or 5 ppm of iNO (INO Therapeutics Inc., Port Allen, La.). Allpatients, healthcare professionals, and investigators were blinded tothe assigned treatment. Inhaled NO was administered via INOvent®delivery system (Datex-Ohmeda, Madison, Wis.) that blended treatment gas(nitrogen or NO at 100-ppm balance nitrogen) 1:20 with ventilator gasesto achieve a target ppm value in the inspiratory limb of the ventilator.

All patients using the iNO delivery system received mechanicalventilatory support. Treatment continued with active or placebo gasuntil one of the following criteria were met: [1] end of trial (28days); [2] death; or [3] adequate oxygenation (arterial oxygensaturation by pulse oximetry [SpO2]≧92% or PaO2 of ≧63 mm Hg) withouttreatment gas at ventilator settings of FiO2≦0.4 and positiveend-expiratory pressure (PEEP) of ≦5 cm H2O. Decreases in treatment gascontinued in 20% decrements (titrated down by 1 ppm for inhaled NO)every 30 minutes until either the treatment gas concentration reached 0%or oxygenation criteria were not satisfied. If oxygenation criteria werenot met, treatment gas concentration was titrated up until they wereagain achieved. Increments of upward titration were determined by theclinician, based on degree of arterial desaturation.

Respiratory Parameters Measured During Hospitalization

Baseline oxygenation measures included PaO₂, arterial partial pressureof CO₂ (PaCO₂), SpO₂, FiO₂, PEEP, PaO₂/FiO₂ ratio, ventricular rate,tidal volume, and mean airway pressure. Respiratory parameters (FiO₂,PEEP, and PaO₂/FiO₂ ratio) were recorded on case report forms every 12hours during mechanical ventilation.

Statistical Methods

Between-group differences in baseline clinical and demographiccharacteristics were assessed with the Fisher's exact test and thechi-square test for categorical variables and with the Wilcoxon rank sumtest for continuous variables. Baseline oxygenation andrespiratory/oxygenation parameters in the two groups were compared usingWilcoxon rank sum tests. The areas under the curve (AUCs) of FiO2, PEEP,and PaO2/FiO2 ratio were calculated using the trapezoidal rule. The nullhypothesis that the respective AUCs were normally distributed wasrejected employing the Shapiro-Wilk test. A Wilcoxon rank sum test wasutilized to assess the differences in each median AUC between treatmentgroups. A p value <0.05 was considered significant.

Results Demographics and Baseline Characteristics

Final disposition of all subjects in the original study and 6-monthfollow-up is shown in FIG. 1. Baseline patient characteristics aresummarized in Table 1. Patients in the two treatment groups were wellmatched for all demographic variables. The only significantbetween-group difference was for weight (76.35±19.16 kg [mean±SD] versus85.67±24.10 kg for iNO and placebo, respectively; p=0.0489). There wereno significant differences between groups with respect to ARDS etiology.There were no differences between groups with respect to severity ofillness, frequency of co-morbid chronic respiratory conditions (i.e.,asthma, chronic obstructive pulmonary disease, or other obstructive orrestrictive lung disease), or use of inhaled corticosteroids. Moresubjects had a history of tobacco use in the iNO group (26 versus 17,p=0.41).

Baseline Oxygenation Parameters

Baseline oxygenation parameters, including PaO₂, PaCO₂, SpO₂, FiO₂,PEEP, and PaO₂/FiO₂ ratio, are summarized in Table 2. The patientsincluded in this analysis were severely ill with mean baseline PaO₂/FiO₂ratios of 140.5±43.4 (iNO) and 136.1±40.4 (placebo). Except for aclinically insignificant difference in SpO₂, there were no significantbetween-group differences with respect to baseline oxygenationparameters.

Baseline Respiratory Parameters

Baseline respiratory parameters, including ventilator rate, tidalvolume, and mean airway pressure are summarized in Table 3. There wereno significant differences between groups for any of these measures.

Respiratory Parameters During Mechanical Ventilation

There were no significant differences between groups for aggregateper-patient changes from baseline parameters in supplemental oxygen,PEEP, or PaO2/FiO2 ratio. However, when calculating the duration ofexposure over the length of mechanical ventilation for total FiO2(6.3+4.5 days versus 7.6+4.7 days for iNO and placebo groups,respectively; p=0.151), total PEEP (96.3+75.9 versus 113.4+81.1 mm Hg,p=0.261) and total PaO2/FiO2 ratio (2637+1729 versus 2950+1774,p=0.358), the iNO group had less cumulative exposure to all threevariables (Table 4).

Summary

Clinical trials evaluating numerous interventions have repeatedly failedto demonstrate significant benefit in decreasing mortality in ARDSpatients. This clinical trial, as well as a meta-analysis of 12randomized controlled trials in ALI or ARDS patients indicated nosignificant benefit of iNO in decreasing mortality.

Inhaled NO did not improve short-term mortality in patients with ARDS

Tables

Table 1 is a summary of baseline demographic and clinicalcharacteristics of the study group.

Table 2 is a summary of baseline oxygenation parameters of the studygroup (placebo versus treated).

Table 3 is a summary of baseline respiratory parameters of the studygroup (placebo versus treated).

Table 4 is a summary of the duration of exposure parameters during gasadministration.

TABLE 1 Baseline Demographic and Clinical Characteristics Inhaled PParameter Placebo NO Value Age, y N 41 51 Mean ± SD 47.8 ± 16.7 45.3 ±15.3 0.494 Range 18.4-84.0 16.8-77.9 Sex, n (%) Male 19 (46%) 25 (49%)0.836 Female 22 (54%) 26 (51%) Race, n (%) Caucasian 35 (85%) 42 (82%)0.847 Black 4 (10%) 5 (10%) Other 2 (5%) 4 (8%) Height, cm N 39 51 Mean± SD 168.7 ± 11.4  169.4 ± 9.2  0.912 Weight, kg N 41 51 Mean ± SD 85.7± 24.1 76.4 ± 19.2 0.049 Causes of ARDS,* n (%) Pneumonia 20 (49%) 15(29%) 0.084 Toxic gas 0 (0%) 0 (0%) 1.000 inhalation Acute 1 (2%) 3 (6%)0.626 pancreatitis Massive blood 5 (12%) 10 (20%) 0.404 transfusion Fatemboli 1 (2%) 2 (4%) 1.000 Aspiration 9 (22%) 9 (18%) 0.610 pneumonitisPulmonary 6 (15%) 12 (24%) 0.307 contusion Postpartum 2 (5%) 0 (0%)0.196 ARDS Multiple 14 (34%) 15 (29%) 0.657 trauma Elective or 9 (22%)20 (39%) 0.114 emergency surgical procedures Preexisting lung 41 (100%)49 (96%) 0.501 disease Preexisting 3 (7%) 6 (11.8%) 0.334 steroid useAsthma 4 (10%) 5 (10%) 1.000 COPD 6 (15%) 6 (12%) 0.761 Tobacco use 17(41%) 26 (51%) 0.405 Other lung 10 (5%) 8 (4%) 0.810 disease^(†) ARDS =acute respiratory distress syndrome; COPD = chronic obstructivepulmonary disorder; NO = nitric oxide. *Patients may have more than onecause of ARDS. ^(†)Patients may have more than one preexisting diseaseincluding: cancer, bronchitis, amiodarone toxicity, and status/post lungresection.

TABLE 2 Baseline Oxygenation Parameters Inhaled P Parameter StatisticsPlacebo NO Value PaO₂, mm Hg N 41 50 Mean ± SD 84.8 ± 21.4 90.6 ± 19.1Median 81 86 0.068 PaCO₂, mm Hg N 41 50 Mean ± SD 39.9 ± 7.7  40.8 ±8.4  Median 41 39 0.728 SpO₂, % N 41 50 Mean ± SD 95.1 ± 2.6  96.5 ±2.6  Median 96 97 0.012 FiO₂ N 41 50 Mean ± SD 0.65 ± 0.13 0.68 ± 0.16Median  1  1 0.517 PEEP, cm H₂O N 41 51 Mean ± SD 9.5 ± 1.7 9.8 ± 2.5Median 10 10 0.748 PaO₂/FiO₂ N 41 50 ratio Mean ± SD 136.1 ± 40.4  140.5± 43.4  Median 132  130  0.774 FiO₂ = inspired oxygen concentration;PaCO₂ = arterial pressure of CO₂; PaO₂ = partial pressure of arterialoxygen; PEEP = positive-end expiratory pressure; SpO₂ = pulse oximetricoxygen saturation.

TABLE 3 Baseline Respiratory Parameters.* Inhaled P Parameter StatisticsPlacebo NO Value Ventilator rate, N 41 50 0.069 breaths/min 14.6 ± 4.413.1 ± 4.2 Tidal volume, mL/kg N 39 49 0.548  9.1 ± 1.7 10.3 ± 2.5 Meanairway pressure, N 37 46 0.488 cm H₂O 18.3 ± 7.1 16.9 ± 5.2 *Values aremean ± SD unless otherwise indicated. NO = nitric oxide.

TABLE 4 Duration of Exposure Parameters During Study GasAdministration.* Inhaled Placebo NO P Parameter (N = 41) (N = 51) ValueInhaled NO, ppm/d 0 114 ± 102 NA FiO₂  7.6 ± 4.7 6.34 ± 4.5  0.151 PEEP,mm Hg 113 ± 81 96.33 ± 75.9  0.261 PaO₂/FiO₂ ratio 195 ± 46 262 ± 4070.358 *Values are mean ± SD unless otherwise indicated. FiO₂ = inspiredoxygen concentration; NO = nitric oxide; PaO₂ = partial pressure ofarterial oxygen; PEEP = positive-end expiratory pressure.

Example 1 Pediatric AHRF Study Synopsis Methodology

This was a prospective, multicenter, randomized, double-blind,placebo-controlled, parallel-group study of the safety and efficacy ofinhaled nitric oxide in pediatric subjects with acute hypoxemicrespiratory failure (AHRF). The subjects were randomized to receiveeither 5 ppm inhaled nitric oxide or placebo.

Number of Subjects (Planned and Analyzed)

350 total subjects (175 per treatment arm) were planned. Because of lowenrollment (and not for safety reasons) the trial was ended when 55subjects were enrolled. A summary of the study population is provided inFIG. 2 and the ventilation settings and gas exchange at enrollment areshown in FIG. 3.

Diagnosis and Main Criteria for Inclusion

Pediatric subjects admitted to the Pediatric Intensive Care Unit (PICU)with AHRF requiring intubation.

Test Product, Dose and Mode of Administration

Nitric Oxide for inhalation at 5 ppm was administered continuously intothe inspiratory limb of the ventilator circuit in mechanicallyventilated subjects using a blinded version of the INOvent® deliverysystem.

Duration of Treatment

Subjects received 100% treatment gas (nitric oxide 5 ppm or placebo[nitrogen gas]) until Day 28 or extubation, whichever occurred first.

Reference Therapy, Dose and Mode of Administration

Placebo consisting of 100% Grade 5 nitrogen gas was administeredcontinuously into the inspiratory limb of the ventilator circuit inmechanically ventilated subjects using a blinded version of the INOvent®delivery system at a rate equivalent to a 5 ppm dose of nitric oxide.

Summary—Conclusions Efficacy Results:

Efficacy data were collected and summarized in place of a full efficacyanalysis. The mean duration of intubation, days in the PICU, andfrequencies of high frequency oscillatory ventilation, extracorporealmembrane oxygenation, and pneumothorax were lower for the nitric oxidegroup than for the placebo group, whereas the duration of supplementaloxygen and the frequency of ventilator-associated pneumonia at dischargewere higher for the nitric oxide group than for the placebo group.

29 patients received placebo and 26 iNO. A summary of the patientrandomization and disposition is shown in FIG. 4. 2 patients randomizedto iNO were withdrawn from the study due to premature termination ofstudy gas. The mean baseline oxygenation index (OI) were 25.6+/−14.9 and22.0+/18.4, placebo and iNO groups, respectively, p=NS. As shown in FIG.5, there was a greater improvement in OI compared to baseline values inthe iNO group at 4 hours (26.1+/−19.5 and 14.3+/−5.9, placebo and iNOgroups, respectively, p=0.09) that became significant at 12 hours(24.5+/−22.0 v. 14.7+/−6.0, p=0.04). By 24 hours there was nosignificant difference in oxygenation between groups (16.7+/−9.9 and15.2+/−10.8, placebo and iNO groups, respectively, p=0.53). Days aliveand ventilator free at 28 days was greater in those randomized to iNO9.1+/−9.5 versus 14.2+/18.1 days (p=0.05). Survival at 28 days was 22 of24 in the iNO group and 21 of 29 in the placebo group (p=0.07) and therate of ECMO free survival was significantly greater in those randomizedto iNO 22 of 24 versus 15 of 29, p<0.01. These results are shown in FIG.6.

Safety Results:

Subjects who received inhaled nitric oxide were no more likely toexperience adverse events (AEs) than were those who received placebo,with 21 subjects in the placebo group (72.4%) reporting 93 AEs and 16subjects in the nitric oxide group (61.5%) reporting 52 AEs. Four AEs,reported by 2 subjects in the placebo group, were suspected to have arelationship to treatment. The frequencies of treatment discontinuationdue to AEs were 6.9% for the placebo group and 3.9% for the nitric oxidegroup. Compared with subjects treated with placebo, subjects treatedwith nitric oxide reported fewer serious AEs during the study (27.6% vs.3.9%) and had a higher survival rate (72.4% vs. 88.5%). No death,serious AE, severe AE, or AE resulting in treatment discontinuation wassuspected to be related to study treatment. The percent methemoglobinlevels were within normal limits in both the placebo and the nitricoxide groups. These levels were well below levels that would havenecessitated discontinuation of treatment.

Conclusion:

The safety profile of inhaled nitric oxide 5 ppm appears to comparefavorably with that of placebo, with regard to methemoglobin levels,frequency of AEs and, particularly, mortality rates. No serious concernsabout the use of inhaled nitric oxide were generated by the results ofthis study, and it appears that inhaled nitric oxide 5 ppm is safe andwell tolerated by children with AHRF.

Unexpectedly, iNO shortened the duration of mechanical ventilation (MV)and improved the rate of survival, both of which approached statisticalsignificance. The rate of ECMO free survival was significantly greaterin those randomized to iNO. It is believed that this is the firstrandomized, non-crossover study to evaluate the impact of iNO onoutcomes in pediatric ARDS. Previous studies incorporated a crossoverdesign, precluding an analysis of outcomes.

Study Details

This was a prospective, multicenter, randomized, double-blind,placebo-controlled, Phase III study to assess the effects of nitricoxide for inhalation in the treatment of acute hypoxic respiratoryfailure (AHRF) in pediatric subjects. The study population consisted ofmale and female pediatric subjects, aged 44 weeks postconceptional ageto 16 years age, who were admitted to the pediatric intensive care unit(PICU) and who required intubation because of AHRF. Theinclusion/exclusion criteria are described in the Patients sectionbelow.

Standardized ventilatory management and weaning procedures were used.Ventilatory management was used based on an “open lung approach” usingpositive end-expiratory pressure (PEEP) to increase lung volume andlimiting tidal volumes to reduce plateau pressures. Subjects receivednitric oxide for inhalation at 5 ppm or placebo (100% Grade 5 nitrogengas) into the inspiratory limb of the ventilator circuit using a blindedversion of the INOvent® delivery system. The subjects were treated untilDay 28 or extubation, whichever occurred first. Subjects were assesseddaily using a spontaneous breathing trial, according to theinstitution's standard of care. Arterial blood gases (ABG), ventilatorsettings, methemoglobin, oxygenation index, systolic blood pressure,diastolic blood pressure, Pediatric Risk of Mortality (PRISM) III score,and subject positioning (prone or supine) were performed/recorded atspecified times during the study. Selected centers also performed plasmacytokine assays, bronchoalveolar lavage fluid (BALF) assays, and a6-month follow-up assessment.

Patients

Inclusion criteria for patients were as follows:

-   -   1. 44 weeks post-conceptional age to 16 years of age    -   2. Oxygenation Index (OI)≧12 cm H₂O/mmHg (as determined by two        separate measurements taken 30 minutes to 4 hours apart)    -   3. Recent chest x-ray (within 24 hours) showing at least        unilateral infiltrates    -   4. Mechanically ventilated (oral or nasopharyngeal) <7 days

Exclusion criteria for patients were as follows:

-   -   1. Immunocompromised    -   2. Received a bone marrow transplant    -   3. Active oncological condition    -   4. Persistent right to left intracardiac shunt    -   5. Cardiovascular surgery within the last 14 days    -   6. Status asthmaticus    -   7. Decision by primary care physician not to provide full        support (futility)    -   8. Received treatment with nitric oxide for inhalation or other        investigational medications with 24 hours prior to study        initiation.    -   9. Chronically ventilated    -   10. Pregnant

Study Design and Schedule of Assessments:

The following assessments were made at baseline: arterial blood gases,ventilator settings, methemoglobin, prone position, PRISM III score,oxygenation index, systolic and diastolic blood pressure,bronchoalveolar lavage fluid assay and plasma cytokine.

The following assessments were made at 4 hours±1 hour after the start oftherapy: arterial blood gases, ventilator settings and methemoglobin.

The following assessments were made at 12 hours±2 hours after the startof therapy: arterial blood gases and ventilator settings.

The following assessments were made at 24 hours±2 hours after the startof therapy: arterial blood gases, ventilator settings, methemoglobin,systolic and diastolic blood pressure and plasma cytokine.

The following assessments were made at 48 hours after the start oftherapy: bronchoalveolar lavage fluid assay.

The following assessments were made at 72 hours after the start oftherapy: plasma cytokine.

The following assessments were made on Day 5 after the start of therapy:bronchoalveolar lavage fluid assay.

The following assessments were made on Day 7 after the start of therapy:plasma cytokine.

Prone positioning was evaluated daily to determine whether prone ≧8hours within a 24-hour period.

The following assessments were made at the end of treatment: plasmacytokine.

The following assessments were made during the follow-up visit:pulmonary function tests (subjects >6 years of age), vital signs(respiratory rate and spot oxygen saturation), and chest X-ray.

Extubation was considered when:

-   -   i. Pressure support of <10 cm H₂O    -   ii. FiO₂<0.60    -   iii. PEEP<6 cm H₂O    -   iv. Nitric oxide has been discontinued for 30 minutes

Extubation occurred within 12 hours of meeting the above criteria. If apatient met the above criteria but was not extubated within 12 hours,the reason (i.e. airway protection, surgery, secretions clearance, etc.)was documented.

Disposition of Patients

Fifty-five subjects were enrolled and randomized to treatment. Theintent-to-treat population consisted of 30 subjects randomized totreatment with placebo and 25 subjects randomized to treatment withnitric oxide 5 ppm. One subject, who was originally randomized toreceive placebo, received nitric oxide in error. This subject wasallowed to continue treatment with nitric oxide throughout the trial.Therefore, the safety population consisted of 29 subjects who receivedplacebo and 26 subjects who received nitric oxide.

Of the 55 subjects enrolled, 21 (72.4%) in the placebo group and 21(80.8%) in the nitric oxide group either completed 28 days of the studyor were successfully extubated. Of the remaining subjects, 8 (27.6%) inthe placebo group and 2 (7.7%) in the nitric oxide group died, and 3subjects in the nitric oxide group discontinued treatment for reasonsother than death. Subject outcome is summarized in Table 5.

TABLE 5 Subject Outcome by Actual Treatment Received Nitric OxidePlacebo 5 ppm Outcome n = 29 n = 26 Successful extubation, n (%) 17(58.6%)  20 (76.9%) Day 28, n (%) 4 (13.8%) 1 (3.8%) Total discontinued,n (%) 8 (27.6%)  5 (19.2%) Best interest of subject, n (%) 0 (0)    1(3.8%) Tracheotomy, n (%) 0 (0)    1 (3.8%) Transferred to burnhospital, n (%) 0 (0)    1 (3.8%) Death, n (%) 8 (27.6%) 2 (7.7%)

Efficacy Evaluation Demographics and Other Baseline Characteristics

The baseline characteristics of the study population are summarized inTable 6.

TABLE 6 Subject Characteristics by Actual Treatment Received NitricOxide Placebo 5 ppm Variable n = 29 n = 26 Sex, n (%) Female 18 (62.1%)12 (46.2%)  Male 11 (37.9%) 14 (53.8%)  Race, n (%) American Indian 1(3.4%) 0 (0)    Asian  3 (10.3%) 1 (3.8%)  Black  8 (27.6%) 7 (26.9%)Hispanic  4 (13.8%) 8 (30.8%) Other 0 (0)     1 (3.8%)  White 13 (44.8%)9 (34.6%) Diagnosis, Other diagnosis  4 (13.8%) 8 (30.8%) ^(a)n (%)Positive pneumonia 11 (37.9%) 10 (38.5%)  culture Negative pneumonia  9(31.0%) 7 (26.9%) culture Sepsis  4 (13.8%) 3 (11.5%) Trauma 2 (6.9%) 0(0)    Unknown 1 (3.4%) 0 (0)    Age (yrs) N 29   26   Mean (SD) 5.8(5.1)     3.8 (4.1)    Median 4.2 2.5 Range (0.1, 16.2) (0.1, 13.5)^(a)Subjects may have more than one diagnosis.

The medical history of the study population is summarized in Table 7.

TABLE 7 Medical History by Actual Treatment Received Subjects withHistory n (%) Nitric Oxide Medical History Placebo 5 ppm Non-operativecardiovascular disease 2 (6.9%) 0 (0)    Chromosomal anomaly  5 (17.2%)4 (15.4%) Cancer 1 (3.4%) 0 (0)    Previous PICU admission 15 (34.5%) 3(11.5%) Pre-PICU CPR 1 (3.4%) 3 (11.5%) Post-operative 1 (3.4%) 1(3.8%)  Diabetic ketoacidosis 1 (3.4%) 0 (0)    Admission from inpatientunit 15 (51.7%) 7 (26.9%) N/A  3 (10.3%) 4 (15.4%) Abbreviations: PICU =pediatric intensive care unit; CPR = cardiopulmonary resuscitation; N/A= not applicable

The concomitant corticosteroid medications are summarized in Table 8.

TABLE 8 Frequencies of Concomitant Corticosteroid Medications by ActualTreatment Received Nitric Oxide Type Coded Steroid Name Placebo^(a) 5ppm^(a) Extubated Dexamethasone  6 (20.7%)    4 (15.4%)Methylprednisolone 0 (0)         1 (3.8%) Methylprednisolone, 1 (3.4%) 0(0) sodium succinate Prednisone 1 (3.4%) 0 (0) Late Lung Dexamethasone 2(6.9%) 0 (0) Disease Fludrocortisone 1 (3.4%) 0 (0) Fluticasone 1 (3.4%)    1 (3.8%) propionate Hydrocortisone 1 (3.4%)     1 (3.8%)Methylprednisolone 2 (6.9%)     2 (7.7%) Methylprednisolone  4 (13.8%)   3 (11.5%) Sodium succinate Prednisolone 1 (3.4%) 0 (0) Prednisone 1(3.4%)    4 (15.4%) Neither Hydrocortisone 1 (3.4%) 0 (0) Prednisone 0(0)         1 (3.8%) ^(a)Subjects with multiple administrations of thesame steroid are counted only once.

Efficacy Results and Tabulations of Individual Patient Data

Full efficacy analyses were not performed. However, efficacy data werecollected and summarized. As shown in Table 9, the mean number of daysof intubation, days in the PICU, and frequencies of high-frequencyoscillatory ventilation (HFOV), extracorporeal membrane oxygenation(ECMO), and pneumothorax were lower for the nitric oxide group than forthe placebo group, whereas the mean number of days of supplementaloxygen and the frequency of VAP at discharge were higher for the nitricoxide group than for the placebo group. The survival rate was 72.4% forthe placebo group and 88.5% for the nitric oxide group.

TABLE 9 Efficacy Data by Actual Treatment Received Nitric Oxide VariablePlacebo 5 ppm Number of days originally intubated, in PICU, and onsupplemental O₂ Number of days originally intubated - 15.8 (11.2)    13.6 (6.8)    Mean (SD) Number of days in PICU - Mean (SD) 25.6(15.4)     17.8 (8.3)    Number of days on supplemental O₂ - 18.8(15.0)     19.6 (13.4)     Mean (SD) Discharge evaluation N 29 26Survival, n (%) 21 (72.4%) 23 (88.5%) Died (cause of death related to 1(3.4%) 0 (0)     pulmonary condition), n (%) Receiving supplemental O₂on Day 28,  8 (27.6%) 11 (42.3%) n (%) Intubated on Day 28, n (%)  5(17.2%) 2 (7.7%) HFOV at any time during treatment, 18 (62.1%) 11(42.3%) n (%) ECMO at any time during treatment,  7 (24.1%) 0 (0)     n(%) Clinical sepsis, n (%)  4 (13.8%)  4 (15.4%) VAP, n (%) 1 (3.4%)  5(19.2%) Pneumothorax, n (%) 10 (34.5%)  3 (11.5%) Abbreviations: PICU =pediatric intensive care unit; HFOV = high-frequency oscillatoryventilation; ECMO = extracorporeal membrane oxygenation; VAP =ventilator-associated pneumonia.

Safety Evaluation Extent of Exposure

The mean duration of treatment was 13 days for subjects in bothtreatment groups (Table 10). Note that one subject from the placebogroup and one subject who received nitric oxide were excluded from thistable because their study drug end date and time were unknown.

TABLE 10 Extent of Exposure by Actual Treatment Received Nitric OxideDuration of treatment (days) Placebo 5 ppm N 28   25   Mean (SD) 13.2(8.8) 12.7 (7.0) Median 10.7 12.7 Range (0.4, 28.1) (2.8, 29.0)

TABLE 11 Durations by Actual Treatment Received Nitric Oxide Placebo 5ppm Duration of treatment (days) N 28   25 Mean (SD) 13.2 (8.8)  12.7(7.0) Median 10.7   12.7 Range (0.4, 28.1) (2.8, 29.0) Days originallyintubated N 19   20 Mean (SD) 15.8 (11.2) 13.6 (6.8) Median 11.9   13.7Range (1.8, 48.8) (3.2, 23.2) Days in PICU N 17   22 Mean (SD) 25.6(15.4) 17.8 (8.3) Median 24.6 17.3 Range (10.3, 55.2)  (4.9, 37.3) Dayson supplemental O₂ N 11   10 Mean (SD) 18.8 (15.0)  19.6 (13.4) Median16.3   18.1 Range (1.8, 57.8) (4.3, 50.7)

Adverse Events

There were 93 AEs reported in 21 of the 29 subjects who received placebo(72.4%). A total of 52 AEs were reported in 16 of the 26 subjects whoreceived nitric oxide (61.5%). Four of the AEs (reported in 2 subjectsin the placebo group) were suspected to have a relationship totreatment.

There were 21 serious adverse events (SAEs) reported in 8 of the 29subjects who received placebo (27.6%) and 2 SAEs reported in 1 of the 26subjects who received nitric oxide (3.9%). There were 27 severe AEsreported in 10 subjects who received placebo (34.5%) and 4 severe AEsreported in 2 subjects who received nitric oxide (7.7%). Two AEsreported in 2 subjects who received placebo (6.9%) and 2 AEs reported in1 subject who received nitric oxide (3.9%) resulted in discontinuationof study treatment. None of the serious or severe AEs was suspected tobe related to study treatment. An overall summary of AEs is presented inTable 12.

TABLE 12 Overview of Adverse Events by Actual Treatment Received NitricOxide Placebo 5 ppm Category^(a) n = 29 n = 26 Subjects treated, n (%)29 (100%)  26 (100%)  Subjects with one or more AEs, n (%) 21 (72.4%) 16(61.5%) Subjects with one or more SAEs, n (%)  8 (27.6%) 1 (3.9%)Subjects withdrawn due to AEs, n (%) 2 (6.9%) 1 (3.9%) Subjects with oneor more severe AEs, n (%) 10 (34.5%) 2 (7.7%) Subjects with one or moreAEs suspected 2 (6.9%) 0 (0)     to be related to study treatment, n (%)Total AEs^(b) 93 52 Total SAEs 21 2 Total AEs leading to discontinuationof 2 2 study treatment Total severe AEs 27 4 Total AEs suspected to berelated to 4 0 study treatment Total SAEs or AEs leading to discontin- 00 uation of study treatment suspected to be related to study treatment^(a)Subjects may fall into more than one category. ^(b)Events arecounted by dictionary-derived term. Events that were reported more thanonce in a given subject are counted only once.

The most frequently reported AEs were hypokalemia and pneumothorax forthe placebo group and bradycardia and hypotension for the nitric oxidegroup. All AEs are presented in Table 14. Adverse events that occurredin 3 or more subjects in either treatment group are summarized in Table13.

TABLE 13 Adverse Events Occurring in Three or More Subjects in EitherTreatment Group by Actual Treatment Received Nitric Oxide^(a) AEPlacebo^(a) 5 ppm Body System (Coded Term) n = 29 n = 26 Metabolism andnutrition Hypokalemia, 6 (20.7%) 2 (7.7%)  disorders n (%) Cardiacdisorders Bradycardia, 2 (6.9%)  3 (11.5%) n (%) Respiratory, thoracicand Pneumothorax, 3 (10.3%) 2 (7.7%)  mediastinal disorders n (%)Vascular disorders Hypotension, 1 (3.4%)  3 (11.5%) n (%) ^(a)Subjectswith multiple occurrences of the same event are counted only once.

TABLE 14 Adverse Events by Actual Treatment Received Nitric Oxide BodySystem Coded Term Placebo^(a) 5 ppm^(a) Blood and lymphatic Anemia 1(3.4%)  1 (3.8%) system disorders Disseminated intravascular 1 (3.4%) 0(0.0) coagulation Hemoglobinemia 0 (0.0)   1 (3.8%) Hemolytic anemia 1(3.4%) 0 (0.0) Leukocytosis 1 (3.4%)  1 (3.8%) Thrombocythemia 2 (6.9%) 1 (3.8%) Thrombocytopenia 1 (3.4%) 0 (0.0) Cardiac disorders Arrhythmia0 (0.0)   1 (3.8%) Bradycardia 2 (6.9%)    3 (11.5%) Cardiac arrest 1(3.4%) 0 (0.0) Eye disorders Ocular icterus 1 (3.4%) 0 (0.0)Gastrointestinal Abdominal distension 1 (3.4%) 0 (0.0) disorders Ascites0 (0.0)   1 (3.8%) Diarrhea 1 (3.4%) 0 (0.0) Gastrointestinal hemorrhage1 (3.4%) 0 (0.0) Pancreatitis 2 (6.9%) 0 (0.0) General disorders andGeneralized edema 1 (3.4%) 0 (0.0) administration site Hypothermia 1(3.4%) 0 (0.0) conditions Multi-organ failure 2 (6.9%) 0 (0.0) Pyrexia 2(6.9%) 0 (0.0) Unevaluable event 1 (3.4%)  2 (7.7%) HepatobiliaryHepatic failure 1 (3.4%) 0 (0.0) disorders Hepatosplenomegaly 0 (0.0)  1 (3.8%) Infections and Bacteremia 0 (0.0)   2 (7.7%) infestationsEmpyema 1 (3.4%) 0 (0.0) Fungemia 0 (0.0)   1 (3.8%) Gangrene 0 (0.0)  1 (3.8%) Lung infection, pseudomonal 1 (3.4%) 0 (0.0) Pneumonia 0(0.0)   1 (3.8%) Pneumonia, aspergillus 1 (3.4%) 0 (0.0) Pneumonia,staphylococcal 1 (3.4%)  1 (3.8%) Pseudomonal sepsis 0 (0.0)   1 (3.8%)Sepsis 1 (3.4%) 0 (0.0) Tracheitis 0 (0.0)   2 (7.7%) Urinary tractinfection 1 (3.4%)  1 (3.8%) Urinary tract infection, fungal 0 (0.0)   1(3.8%) Injury, poisoning and Device failure 1 (3.4%) 0 (0.0) proceduralHemothorax 1 (3.4%) 0 (0.0) complications Skin injury 1 (3.4%) 0 (0.0)Subdural hematoma 1 (3.4%) 0 (0.0) Investigations Bacteria, blood 1(3.4%)  1 (3.8%) Bacteria, sputum 2 (6.9%) 0 (0.0) Bronchoalveolarlavage 1 (3.4%)  1 (3.8%) C-reactive protein increased 1 (3.4%) 0 (0.0)Fungus culture positive 2 (6.9%) 0 (0.0) Investigations Fungus urinetest positive 1 (3.4%) 0 (0.0) (continued) Oxygen saturation decreased 1(3.4%)  2 (7.7%) Urine output decreased 1 (3.4%)  1 (3.8%) White bloodcell count increased 1 (3.4%) 0 (0.0) Metabolism and Acidosis 0 (0.0)  1 (3.8%) nutrition disorders Diabetic ketoacidosis 1 (3.4%) 0 (0.0)Feeding disorder 1 (3.4%) 0 (0.0) Hyperammonemia 1 (3.4%) 0 (0.0)Hypercalcemia 1 (3.4%)  1 (3.8%) Hyperchloremia 0 (0.0)   1 (3.8%)Hyperglycemia 0 (0.0)   1 (3.8%) Hyperkalemia 2 (6.9%)  1 (3.8%)Hyperlipidemia 1 (3.4%) 0 (0.0) Hypernatremia 0 (0.0)   2 (7.7%)Hypocalcemia 0 (0.0)   1 (3.8%) Hypochloremia 1 (3.4%) 0 (0.0)Hypokalemia  6 (20.7%)  2 (7.7%) Metabolic acidosis 1 (3.4%) 0 (0.0)Metabolic alkalosis 1 (3.4%)  1 (3.8%) Nervous system Brain edema 1(3.4%) 0 (0.0) disorders Cerebral artery occlusion 1 (3.4%) 0 (0.0)Intracranial pressure increased 1 (3.4%) 0 (0.0) Psychiatric disordersAgitation 2 (6.9%)  2 (7.7%) Renal and urinary Bladder distension 1(3.4%) 0 (0.0) disorders Hematuria 1 (3.4%) 0 (0.0) Oliguria 1 (3.4%) 0(0.0) Renal failure 2 (6.9%)  1 (3.8%) Renal failure, acute 1 (3.4%) 0(0.0) Renal impairment 1 (3.4%) 0 (0.0) Respiratory, thoracic Apnea 0(0.0)   1 (3.8%) and mediastinal Hemopneumothorax 1 (3.4%) 0 (0.0)disorders Hypercapnia 1 (3.4%) 0 (0.0) Hypoxia 1 (3.4%) 0 (0.0) Pleuraleffusion 1 (3.4%) 0 (0.0) Pneumomediastinum 1 (3.4%) 0 (0.0)Pneumothorax  3 (10.3%)  2 (7.7%) Pulmonary hemorrhage 2 (6.9%) 0 (0.0)Pulmonary hypertension 1 (3.4%) 0 (0.0) Respiratory acidosis 1 (3.4%) 0(0.0) Respiratory failure Skin and subcutaneous Pruritus 1 (3.4%) 0(0.0) tissue disorders Surgical and medical Chest tube insertion 0(0.0)   1 (3.8%) procedures Medical device removal 1 (3.4%) 0 (0.0)Vascular disorders Deep vein thrombosis 0 (0.0)   2 (7.7%) Hemorrhage 1(3.4%) 0 (0.0) Vascular disorders Hypertension 2 (6.9%) 0 (0.0)(continued) Hypotension 1 (3.4%)    3 (11.5%) Labile blood pressure 1(3.4%) 0 (0.0) ^(a)Subjects with multiple occurrences of the same eventare counted only once.

Four AEs, reported in 2 subjects in the placebo group, were suspected tobe related to study treatment (one subject had agitation andhyperlipidemia; another subject had hyperammonemia and increasedC-reactive protein). All of these were non-serious AEs that were mild,and all but hyperammonemia had resolved by the end of the study (seeTable 15).

TABLE 15 Adverse Events by Actual Treatment Received and by Relationshipto Study Treatment Not Suspected^(a) Suspected^(a) Nitric Nitric OxideOxide Body System Coded Term Placebo 5 ppm Placebo 5 ppm Blood andAnemia 1 (3.4%)  1 (3.8%) 0 (0.0) 0 (0.0) lymphatic system Disseminatedintravascular 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) disorders coagulationHemoglobinemia 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0) Hemolytic anemia 1(3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Leukocytosis 1 (3.4%)  1 (3.8%) 0 (0.0) 0(0.0) Thrombocythemia 2 (6.9%)  1 (3.8%) 0 (0.0) 0 (0.0)Thrombocytopenia 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Cardiac disordersArrhythmia 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0) Bradycardia 2 (6.9%)    3(11.5%) 0 (0.0) 0 (0.0) Cardiac arrest 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)Eye disorders Ocular icterus 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)Gastrointestinal Abdominal distension 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)disorders Ascites 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0) Diarrhea 1 (3.4%) 0(0.0) 0 (0.0) 0 (0.0) Gastrointestinal hemorrhage 1 (3.4%) 0 (0.0) 0(0.0) 0 (0.0) Pancreatitis 2 (6.9%) 0 (0.0) 0 (0.0) 0 (0.0) Generaldisorders Generalized edema 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) andadministration Hypothermia 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) siteconditions Multi-organ failure 2 (6.9%) 0 (0.0) 0 (0.0) 0 (0.0) Pyrexia2 (6.9%) 0 (0.0) 0 (0.0) 0 (0.0) Unevaluable event 1 (3.4%)  2 (7.7%) 0(0.0) 0 (0.0) Hepatobiliary Hepatic failure 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) disorders Hepatosplenomegaly 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0)Infections and Bacteremia 0 (0.0)   2 (7.7%) 0 (0.0) 0 (0.0)infestations Empyema 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Fungemia 0 (0.0)  1 (3.8%) 0 (0.0) 0 (0.0) Grangrene 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0)Lung infection, pseudomonal 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Pneumonia 0(0.0)   1 (3.8%) 0 (0.0) 0 (0.0) Pneumonia, aspergillus 1 (3.4%) 0 (0.0)0 (0.0) 0 (0.0) Pneumonia, staphylococcal 1 (3.4%)  1 (3.8%) 0 (0.0) 0(0.0) Pseudomonal sepsis 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0) Sepsis 1(3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Tracheitis 0 (0.0)   2 (7.7%) 0 (0.0) 0(0.0) Urinary tract infection 1 (3.4%)  1 (3.8%) 0 (0.0) 0 (0.0) Urinarytract infection, fungal 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0) Injury,poisoning Device failure 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) and proceduralHemothorax 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) complications Skin injury 1(3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Subdural hematoma 1 (3.4%) 0 (0.0) 0(0.0) 0 (0.0) Investigations Bacteria, blood 1 (3.4%)  1 (3.8%) 0 (0.0)0 (0.0) Bacteria, sputum 2 (6.9%) 0 (0.0) 0 (0.0) 0 (0.0)Bronchoalveolar lavage 1 (3.4%)  1 (3.8%) 0 (0.0) 0 (0.0) C-reactiveprotein increased 0 (0.0)  0 (0.0)  1 (3.4%) 0 (0.0) Fungus culturepositive 2 (6.9%) 0 (0.0) 0 (0.0) 0 (0.0) Fungus urine test positive 1(3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Oxygen saturation decreased 1 (3.4%)  2(7.7%) 0 (0.0) 0 (0.0) Urine output decreased 1 (3.4%)  1 (3.8%) 0 (0.0)0 (0.0) White blood cell count increased 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) Metabolism and Acidosis 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0)nutrition disorders Diabetic ketoacidosis 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) Feeding disorder 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Hyperammonemia 0(0.0)  0 (0.0)  1 (3.4%) 0 (0.0) Hypercalcemia 1 (3.4%)  1 (3.8%) 0(0.0) 0 (0.0) Hyperchloremia 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0)Hyperglycemia 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0) Hyperkalemia 2 (6.9%) 1 (3.8%) 0 (0.0) 0 (0.0) Hyperlipidemia 0 (0.0)  0 (0.0)  1 (3.4%) 0(0.0) Hypernatremia 0 (0.0)   2 (7.7%) 0 (0.0) 0 (0.0) Metabolism andHypocalcemia 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0) nutrition disordersHypochloremia  1 (3.4%)) 0 (0.0) 0 (0.0) 0 (0.0) (continued) Hypokalemia 6 (20.7%)  2 (7.7%) 0 (0.0) 0 (0.0) Metabolic acidosis 1 (3.4%) 0 (0.0)0 (0.0) 0 (0.0) Metabolic alkalosis 1 (3.4%)  1 (3.8%) 0 (0.0) 0 (0.0)Nervous system Brain edema 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) disordersCerebral artery occlusion 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Intracranialpressure increased 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Psychiatricdisorders Agitation 1 (3.4%)  2 (7.7%)  1 (3.4%) 0 (0.0) Renal andurinary Bladder distension 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) disordersHematuria 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Oliguria 1 (3.4%) 0 (0.0) 0(0.0) 0 (0.0) Renal failure 2 (6.9%)  1 (3.8%) 0 (0.0) 0 (0.0) Renalfailure, acute 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Renal impairment 1(3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Respiratory, Apnea 0 (0.0)   1 (3.8%) 0(0.0) 0 (0.0) thoracic and Hemopneumothorax 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) mediastinal Hypercapnia 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) disordersHypoxia 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Respiratory, Pleural effusion 1(3.4%) 0 (0.0) 0 (0.0) 0 (0.0) thoracic and Pneumomediastinum 1 (3.4%) 0(0.0) 0 (0.0) 0 (0.0) mediastinal Pneumothorax  3 (10.3%)  2 (7.7%) 0(0.0) 0 (0.0) disorders Pulmonary hemorrhage 2 (6.9%) 0 (0.0) 0 (0.0) 0(0.0) (continued) Pulmonary hypertension 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) Respiratory acidosis 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Respiratoryfailure 1 (3.4%)  1 (3.8%) 0 (0.0) 0 (0.0) Skin and subcutaneousPruritus 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) tissue disorders Surgical andmedical Chest tube insertion 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0)procedures Medical device removal 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)Vascular disorders Deep vein thrombosis 0 (0.0)   2 (7.7%) 0 (0.0) 0(0.0) Hemorrhage 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Hypertension 2 (6.9%)0 (0.0) 0 (0.0) 0 (0.0) Hypotension 1 (3.4%)    3 (11.5%) 0 (0.0) 0(0.0) Labile blood pressure 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)^(a)Subjects with multiple occurrences of the same event are countedonly once.

Deaths, Other Serious Adverse Events, and Other Significant AdverseEvents

Eleven subjects died during the study or follow-up period. Eight diedduring treatment with placebo, 2 died during treatment with nitricoxide, and 1 died during the follow-up period after treatment withnitric oxide. All subjects who died are identified in Table 16. Foursubjects who died had no AE listed where “death” was the outcome, and 1of these subjects died after the treatment period. A summary of AEs inwhich death was the outcome is provided in Table 17. None of the AEs inwhich death was the outcome was suspected of being related to the studytreatment (Table 18).

TABLE 16 Identification of All Subjects Who Died Subject Age Number Sex(y) AE^(a) in Which Death was the Outcome Placebo 1005 F 7.2 Sepsis 1006M 11.4 Cardiac arrest 1011 F 13.8 Brain edema, hemolytic anemia, hepaticfailure, pancreatitis, renal failure, renal impairment, respiratoryfailure,^(b) hypoxia^(b) 3007 M 1.7 No AE listed in which death was theoutcome 3009 M 15.5 No AE listed in which death was the outcome 6001 M11.5 Diabetic ketoacidosis, multi-organ failure 8003 M 14.7 Intracranialpressure increased 8004 M 2.9 Pneumonia Aspergillus pulmonary hemorrhageNitric Oxide  2001A^(c) F 1.5 No AE listed in which death was theoutcome 2007 F 8.6 No AE listed in which death was the outcome 3003 M3.2 Bradycardia, hypotension ^(a)All AEs in which death was the outcomewere SAEs. ^(b)Death was not listed as the outcome of this SAE. ^(c)Thesubject died after the treatment period.

TABLE 17 Adverse Events in Which Death was the Outcome by ActualTreatment Received Nitric Oxide Body System Coded Term Placebo^(a) 5ppm^(a) Blood and lymphatic Hemolytic anemia 1 (3.4%) 0 (0.0) systemdisorders Cardiac disorders Bradycardia 0 (0.0)   1 (3.8%) Cardiacarrest 1 (3.4%) 0 (0.0) Gastrointestinal Pancreatitis 1 (3.4%) 0 (0.0)disorders General disorders and Multi-organ failure 1 (3.4%) 0 (0.0)administration site conditions Hepatobiliary Hepatic failure 1 (3.4%) 0(0.0) disorders Infections and Pneumonia, 1 (3.4%) 0 (0.0) infestationsaspergillus Sepsis 1 (3.4%) 0 (0.0) Metabolism and Diabetic ketoacidosis1 (3.4%) 0 (0.0) nutrition disorders Nervous system Brain edema 1 (3.4%)0 (0.0) disorders Intracranial pressure 1 (3.4%) 0 (0.0) increased Renaland urinary Renal failure 1 (3.4%) 0 (0.0) disorders Renal impairment 1(3.4%) 0 (0.0) Respiratory, thoracic Pulmonary 1 (3.4%) 0 (0.0) andmediastinal hemorrhage disorders Vascular disorders Hypotension 0 (0.0)  1 (3.8%) ^(a)Subjects with multiple occurrences of the same event arecounted only once.

TABLE 18 Adverse Events in Which Death was the Outcome by ActualTreatment Received and by Relationship to Treatment Not Suspected^(a)Suspected^(a) Nitric Nitric Oxide Oxide Body System Coded Term Placebo 5ppm Placebo 5 ppm Blood and Hemolytic anemia 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) lymphatic system disorders Cardiac disorders Bradycardia 0 (0.0)  1 (3.8%) 0 (0.0) 0 (0.0) Cardiac arrest 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) Gastrointestinal Pancreatitis 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)disorders General disorders Multi-organ failure 1 (3.4%) 0 (0.0) 0 (0.0)0 (0.0) and administration site conditions Hepatobiliary Hepatic failure1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) disorders Infections and Pneumonia, 1(3.4%) 0 (0.0) 0 (0.0) 0 (0.0) infestations aspergillus Sepsis 1 (3.4%)0 (0.0) 0 (0.0) 0 (0.0) Metabolism and Diabetic 1 (3.4%) 0 (0.0) 0 (0.0)0 (0.0) nutrition disorders ketoacidosis Nervous system Brain edema 1(3.4%) 0 (0.0) 0 (0.0) 0 (0.0) disorders Intracranial 1 (3.4%) 0 (0.0) 0(0.0) 0 (0.0) pressure increased Renal and urinary Renal failure 1(3.4%) 0 (0.0) 0 (0.0) 0 (0.0) disorders Renal impairment 1 (3.4%) 0(0.0) 0 (0.0) 0 (0.0) Repiratory, Pulmonary 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) thoracic and hemorrhage mediastinal disorders Vascular disordersHypotension 0 (0.0)   1 (3.8%) 0 (0.0) 0 (0.0) ^(a)Subjects withmultiple occurrences of the same event are counted only once.

There were 21 SAEs reported in 8 of the 29 subjects who received placebo(27.6%) and 2 SAEs reported in 1 of the 26 subjects who received nitricoxide (3.9%). All subjects with SAEs are identified in Table 19. No SAEwas reported by more than 1 subject in either treatment group (Table20), and no SAE had a suspected relationship to study treatment (Table21).

TABLE 19 Identification of All Subjects with Serious Adverse EventsSubject Age Action/Reported Number Sex (y) SAE Outcome Placebo 1005 F7.2 Sepsis DC/death 1006 M 11.4 Cardiac arrest Con med/death 1011 F 13.8Brain edema, hemolytic Con med/death anemia, hepatic failure,pancreatits, renal failure, renal impairment Respiratory failure,Extended hypoxia hospitalization/ improved 3007 M 1.7 Subdural hematomaSurgical intervention/ recovered 3008 M 4.2 Hemothorax, unevaluableSurgical event (severe respiratory intervention/ air-leak syndrome),renal recovered failure acute Cerebral artery occlusion Surgicalintervention/ improved 6001 M 11.5 Diabetic ketoacidosis, Noaction/death multi-organ failure Hemopneumothorax Surgical intervention/improved 8003 M 14.7 Intracranial pressure Con med/death increased 8004M 2.9 Pulmonary hemorrhage DC/death Pneumonia Aspergillus Con med/deathNitric Oxide 3003 M 3.2 Bradycardia, hypotension DC/death Abbreviations:DC = discontinued treatment; Con med = concomitant medication taken

TABLE 20 Serious Adverse Events by Actual Treatment Received NitricOxide Body System Coded Term Placebo^(a) 5 ppm^(a) Blood and lymphaticHemolytic anemia 1 (3.4%) 0 (0.0) system disorders Cardiac disordersBradycardia 0 (0.0)   1 (3.8%) Cardiac arrest 1 (3.4%) 0 (0.0)Gastrointestinal Pancreatitis 1 (3.4%) 0 (0.0) disorders Generaldisorders Multi-organ failure 1 (3.4%) 0 (0.0) and administrationUnevaluable event 1 (3.4%) 0 (0.0) site conditions Hepatobiliarydisorders Hepatic failure 1 (3.4%) 0 (0.0) Infections and Pneumonia, 1(3.4%) 0 (0.0) infestations aspergillus Sepsis 1 (3.4%) 0 (0.0) Injury,poisoning and Hemothorax 1 (3.4%) 0 (0.0) procedural complicationsSubdural hematoma 1 (3.4%) 0 (0.0) Metabolism and Diabetic ketoacidosis1 (3.4%) 0 (0.0) nutrition disorders Nervous system disorders Brainedema 1 (3.4%) 0 (0.0) Cerebral artery 1 (3.4%) 0 (0.0) occlusionIntracranial pressure 1 (3.4%) 0 (0.0) increased Renal and urinary Renalfailure 1 (3.4%) 0 (0.0) disorders Renal failure, acute 1 (3.4%) 0 (0.0)Renal impairment 1 (3.4%) 0 (0.0) Respiratory, thoracic Hemopneumothorax1 (3.4%) 0 (0.0) and mediastinal Hypoxia 1 (3.4%) 0 (0.0) disordersPulmonary 1 (3.4%) 0 (0.0) hemorrhage Respiratory failure 1 (3.4%) 0(0.0) Vascular disorders Hypotension 0 (0.0)   1 (3.8%) ^(a)Subjectswith multiple occurrences of the same event are counted only once.

TABLE 21 Serious Adverse Events by Actual Treatment Received and byRelationship to Study Treatment Not Suspected^(a) Suspected^(a) NitricNitric Oxide Oxide Body System Coded Term Placebo 5 ppm Placebo 5 ppmBlood and lymphatic Hemolytic anemia 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)system disorders Cardiac disorders Bradycardia 0 (0.0)   1 (3.8%) 0(0.0) 0 (0.0) Cardiac arrest 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)Gastrointestinal Pancreatitis 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) disordersGeneral disorders and Multi-organ failure 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) administration site Unevaluable event 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) conditions Hepatobiliary Hepatic failure 1 (3.4%) 0 (0.0) 0 (0.0)0 (0.0) disorders Infections and Pneumonia, 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) infestations aspergillus Sepsis 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)Injury, poisoning and Hemothorax 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)procedural Subdural hematoma 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)complications Metabolism and Diabetic 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)nutrition disorders ketoacidosis Nervous system Brain edema 1 (3.4%) 0(0.0) 0 (0.0) 0 (0.0) disorders Cerebral artery 1 (3.4%) 0 (0.0) 0 (0.0)0 (0.0) occlusion Intracranial pressure 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)increased Renal and urinary Renal failure 1 (3.4%) 0 (0.0) 0 (0.0) 0(0.0) disorders Renal failure, acute 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0)Renal impairment 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) Respiratory, thoracicHemopneumothorax 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) and mediastinalHypoxia 1 (3.4%) 0 (0.0) 0 (0.0) 0 (0.0) disorders Pulmonary 1 (3.4%) 0(0.0) 0 (0.0) 0 (0.0) hemorrhage Respiratory failure 1 (3.4%) 0 (0.0) 0(0.0) 0 (0.0) Vascular disorders Hypotension 0 (0.0)   1 (3.8%) 0 (0.0)0 (0.0) ^(a)Subjects with multiple occurrences of the same event arecounted only once.

Two AEs reported in 2 of the 29 subjects who received placebo (6.9%) and2 AEs reported in 1 of the 26 subjects who received nitric oxide (3.9%)resulted in discontinuation of study treatment. All subjects in whomstudy treatment was discontinued because of one or more AEs areidentified in Table 22. No AE that resulted in treatment discontinuationwas reported by more than 1 subject in either treatment group (Table23), and none had a suspected relationship to study treatment (Table24).

TABLE 22 Identification of All Subjects in Whom Study Treatment wasDiscontinued Because of One or More Adverse Events Subject AgeAction/Reported Number Sex (y) SAE Outcome Placebo 1005 F 7.2 Sepsis^(a)DC/death 8004 M 2.9 Pulmonary DC/death hemorrhage^(a) Nitric Oxide 3003M 3.2 Bradycardia^(a), DC/death hypotension^(a) Abbreviations: DC =discontinued treatment ^(a)SAE

TABLE 23 Adverse Events Where Treatment was Stopped by Actual TreatmentReceived Nitric Oxide Body System Coded Term Placebo^(a) 5 ppm^(a)Cardiac disorders Bradycardia 0 (0.0)  1 (3.8%) Infections and Sepsis 1(3.4%) 0 (0.0)  infestations Respiratory, thoracic Pulmonary 1 (3.4%) 0(00)   and mediastinal hemorrhage disorders Vascular disordersHypotension 0 (0.0)  1 (3.8%) ^(a)Subjects with multiple occurrences ofthe same event are counted only once.

TABLE 24 Adverse Events Where Treatment was Stopped by Actual StudyTreatment Received and by Relationship to Study Treatment NotSuspected^(a) Suspected^(a) Nitric Nitric Oxide Oxide Body System CodedTerm Placebo 5 ppm Placebo 5 ppm Cardiac Bradycardia 0 (0.0)  1 (3.8%) 0(0.0) 0 (0.0) disorders Infections and Sepsis 1 (3.4%) 0 (0.0)  0 (0.0)0 (0.0) infestations Respiratory, Pulmonary 1 (3.4%) 0 (0.0)  0 (0.0) 0(0.0) thoracic and hemorrhage mediastinal disorders Vascular Hypotension0 (0.0)  1 (3.8%) 0 (0.0) 0 (0.0) disorders ^(a)Subjects with multipleoccurrences of the same event are counted only once.

Clinical Laboratory Evaluation

Percent methemoglobin levels were obtained at baseline and at Hours 4and 24. The percent methemoglobin levels were within normal limits inboth the placebo and the nitric oxide groups. These levels were wellbelow levels that would have necessitated discontinuation of treatment.Percent methemoglobin levels are summarized in Table 25.

TABLE 25 Summary of Methemoglobin (%) Levels by Actual TreatmentReceived Baseline 4 Hours 24 Hours Nitric Nitric Nitric Oxide OxideOxide Placebo 5 ppm Placebo 5 ppm Placebo 5 ppm N 22 22 27 25 24 23 Mean(SD) 0.63 (0.33) 0.56 (0.35) 0.67 (0.27) 0.64 (0.33) 0.52 (0.33) 0.52(0.37) Median   0.8   0.5   0.7   0.8   0.6   0.5 Range (0.0, 1.0) (0.0,1.0) (0.0, 1.0) (0.0, 1.0) (0.0, 0.9) (0.0, 1.0)

Vital Signs, Physical Findings, and Other Observations Related to Safety

Mean systolic and diastolic blood pressure increased slightly frombaseline in both groups at 24 hours. Descriptive statistics for systolicand diastolic blood pressure, which were taken both at baseline and at24 hours, are summarized Table 26.

TABLE 26 Descriptive Statistics for Vital Signs by Actual TreatmentReceived Nitric Oxide Vital Sign Value Placebo 5 ppm Baseline SystolicBP (mmHg) N 29   25   Mean (SD) 93.4 (17.6) 94.4 (17.4) Median 95.0 95.5Range (52.0, 128.0) (63.0, 123.0) Diastolic BP (mmHg) N 29   26   Mean(SD) 48.5 (12.5) 54.6 (11.6) Median 47.0 55.5 Range (21.0, 77.0)  (38.0,73.0)  24 Hours Systolic BP (mmHg) N 28   24   Mean (SD) 95.9 (17.8)97.9 (21.7) Median 97.0 103.0 Range (69.0, 132.0) (50.0, 136.0)Diastolic BP (mmHg) N 28   24   Mean (SD) 52.5 (9.9)  56.0 (12.7) Median52.5 54.5 Range (30.0, 72.0)  (39.0, 90.0) 

Descriptive statistics for the PRISM III Worksheet values taken atbaseline (systolic blood pressure, temperature, heart rate, pupilreactivity, Glasgow Coma Scale, pH, carbon dioxide pressure [pCO₂],total carbon dioxide, partial pressure of oxygen [PaO₂], glucose,potassium, blood urea nitrogen, creatinine, white blood cell count,platelet count, prothrombin time, and partial thromboplastin time) aresummarized in Table 27.

TABLE 27 Baseline PRISM 3 Worksheet Statistics, by Actual TreatmentReceived Nitric Oxide Placebo 5 ppm Systolic BP (mmHg) N 29 26 Mean (SD)85.0 (27.0) 82.8 (23.8) Median   81.0   77.5 Range  (0.0, 137.0)  (51.0,142.0) Temperature (C.) N 29 26 Mean (SD) 37.8 (1.4)  37.6 (1.5)  Median  38.2   38.1 Range (34.6, 40.0) (34.6, 40.0) Heart rate (bpm) N 29 26Mean (SD) 155.3 (37.5)  157.9 (37.9)  Median  164.0  160.0 Range  (0.0,199.0)  (74.0, 216.0) Pupils Both Reactive 24 (82.8%) 20 (76.9%) 1 Fixed1 (3.4%) 0 (0%)   Both Fixed  4 (13.8%) 2 (7.7%) Glasgow Coma Scale N 1915 Mean (SD) 8.1 (4.7) 8.7 (4.4) Median   8.0   9.0 Range  (3.0, 15.0) (3.0, 15.0) pH (low) N 27 23 Mean (SD) 7.3 (0.1) 7.3 (0.1) Median   7.3  7.3 Range (7.0, 7.5) (7.0, 7.6) pH (high) N 26 21 Mean (SD) 7.4 (0.1)7.4 (0.1) Median   7.4   7.4 Range (7.2, 7.6) (7.2, 7.6) pCO₂ (mmHg) N28 26 Mean (SD) 60.4 (19.1) 56.7 (19.3) Median   59.2   53.0 Range (34.1, 113.2)  (24.8, 102.0) Total CO₂ low (mEq/L) N 27 22 Mean (SD)25.6 (6.2)  25.5 (5.6)  Median   24.0   25.0 Range (14.0, 38.0) (15.0,36.0) Total CO₂ high (mEq/L) N 23 18 Mean (SD) 28.6 (6.0)  26.5 (4.5) Median   29.0   27.0 Range (18.0, 40.0) (14.0, 32.0) PaO₂ (mmHg) N 26 20Mean (SD) 56.4 (12.7) 60.2 (13.6) Median   55.5   55.0 Range (33.0,77.0) (45.0, 91.0) Glucose (mg/dL) N 27 24 Mean (SD) 160.1 (75.0)  165.8(105.2) Median  136.0  139.0 Range  (52.0, 328.0)  (78.0, 543.0)Potassium (mEq/L) N 28 25 Mean (SD) 4.1 (0.9) 4.0 (0.7) Median   4.1  3.9 Range (2.1, 6.2) (2.6, 5.4) BUN (mg/dL) N 27 23 Mean (SD) 14.9(17.1) 13.8 (14.4) Median   10.0   9.0 Range  (4.0, 75.0)  (1.0, 67.0)Creatinine (mg/dL) N 27 23 Mean (SD) 0.7 (0.8) 0.6 (0.5) Median   0.5  0.4 Range (0.1, 4.0) (0.2, 2.4) White blood cell count (μL) N 23 19Mean (SD)  1142.5 (5,418.7) 11.1 (16.1) Median   11.3   7.5 Range     (1.1, 26,000.0^(a))  (0.8, 75.8) Platelet Count (μL) N 23 19 Mean(SD) 223.6 (114.2) 209.5 (105.1) Median  225.0  237.0 Range  (52.0,534.0)  (2.0, 394.0) Prothrombin Time (s) N 17 10 Mean (SD) 17.5 (7.0) 15.1 (6.1)  Median 16.3   15.3 Range  (1.2, 30.1)  (1.4, 26.5) PartialThromboplastin Time (s) N 17 10 Mean (SD) 45.8 (40.7) 39.9 (9.3)  Median  32.2   37.2 Range  (22.8, 197.3) (29.9, 61.1) Abbreviations: BUN =blood urea nitrogen; pCO₂ = carbon dioxide pressure; PaO₂ = partialpressure of oxygen ^(a)High white blood cell count value verified oncase report form

Descriptive statistics for the respiratory values are summarized inTable 28. Oxygen status was determined at screening only. Respiratoryvalues in the HFOV category were obtained at baseline, 4 hours, 12hours, and 24 hours. Respiratory values in the categories conventionalmechanical ventilation [CMV] and ABG were obtained at baseline, 4 hours,12 hours, 24 hours, and at extubation.

Of 6 subjects in whom a chest x-ray was performed, 4 (13.8%), all ofwhom were in the placebo group, had evidence of chronicchanges/persistent infiltrates.

TABLE 28 Descriptive Statistics for Respiratory Values by ActualTreatment Received Nitric oxide Placebo 5 ppm Screening Oxygen StatusOxygen Index 1 N 28 26 Mean (SD) 26.9 (15.0) 22.2 (8.2)  Median   25.4  21.3 Range (12.0, 90.9) (12.4, 44.2) Oxygen Index 2 N 29 26 Mean (SD)27.1 (15.4) 22.7 (7.9)  Median   23.8   23.0 Range (13.4, 82.9) (12.6,40.0) Baseline CMV Rate (/min) N 20 19 Mean (SD) 26.1 (5.9)  27.1 (6.6) Median   24.0   28.0 Range (16.0, 36.0) (15.0, 40.0) Pplat (cmH₂O) N  6 3 Mean (SD) 32.0 (3.3)  28.7 (1.5)  Median   33.0   29.0 Range (27.0,36.0) (27.0, 30.0) PEEP (cmH₂O) N 20 19 Mean (SD) 10.9 (2.8)  10.6(2.9)  Median   10.0   10.0 Range  (7.0, 18.0)  (5.0, 16.0) FiO₂ (%) N20 19 Mean (SD) 71.0 (22.8) 83.5 (20.3) Median   70.0   90.0 Range (1.0, 100.0)  (40.0, 100.0) Baseline CMV MAP (cmH₂O) (continued) N 2019 Mean (SD) 20.1 (5.6)  17.8 (3.7)  Median   18.5   18.0 Range (11.0,34.0) (11.8, 24.0) Set Vt (mL) N 14 12 Mean (SD) 186.5 (156.2) 129.3(74.3)  Median  127.5  110.0 Range  (40.0, 550.0)  (69.0, 348.0)Inspiratory time (s) N 20 19 Mean (SD) 0.9 (0.3) 0.8 (0.3) Median   0.9  0.8 Range (0.5, 1.5) (0.5, 1.5) HFOV Hertz (min) N  9  7 Mean (SD) 7.0(2.3) 7.7 (1.4) Median   8.0   7.0 Range  (4.0, 10.0)  (6.0, 10.0) MAP(cmH₂O) N  9  7 Mean (SD) 27.7 (4.5)  26.3 (2.6)  Median   26.0   26.4Range (23.0, 34.8) (22.0, 30.0) Baseline HFOV Inspiratory Time (s)(continued) N  9  7 Mean (SD)  7.6 (14.4)  5.0 (12.4) Median   0.3   0.3Range  (0.3, 33.0)  (0.0, 33.0) FiO₂ (%) N  9  7 Mean (SD) 92.6 (10.6)53.6 (22.4) Median  100.0   40.0 Range  (75.0, 100.0) (35.0, 95.0) deltaP (cmH₂O) N  9  6 Mean (SD) 48.3 (14.3) 47.2 (11.2) Median   43.0   46.0Range (37.0, 81.0) (35.0, 60.0) ABG pH N 29 25 Mean (SD) 7.4 (0.1) 7.4(0.1) Median   7.4   7.4 Range (7.1, 7.5) (7.2, 7.6) PaO₂ (mmHg) N 29 25Mean (SD) 72.4 (23.3) 67.5 (13.1) Median   66.0   63.0 Range  (41.0,150.8) (45.0, 97.0) Baseline ABG SaO₂ (%) (continued) N 29 25 Mean (SD)92.1 (4.6)  92.8 (3.5)  Median   93.0   92.0 Range (81.0, 98.5)  (86.0,100.0) PaCO₂ (mmHg) N 29 25 Mean (SD) 50.7 (15.0) 45.3 (11.1) Median  48.3   46.5 Range  (29.0, 101.0) (25.2, 75.6) BE (mEq/L) N 29 25 Mean(SD) 1.9 (6.2) 0.2 (5.3) Median   1.4   0.4 Range (−7.4, 13.0) (−13.2,11.0)  HCO₃ (mEq/L) N 29 25 Mean (SD) 27.7 (5.8)  25.6 (5.0)  Median  27.5   26.0 Range (18.0, 38.3) (14.6, 35.9) 4 Hours CMV Rate (/min) N21 18 Mean (SD) 24.7 (6.7)  25.5 (5.9)  Median   24.0   27.0 Range(10.0, 36.0) (15.0, 40.0) CMV 4 Hours Pplat (cmH₂O) (continued) N  6  3Mean (SD) 29.5 (5.8)  29.0 (2.0)  Median   30.0   29.0 Range (23.0,35.0) (27.0, 31.0) PEEP (cmH₂O) N 21 18 Mean (SD) 11.2 (2.4)  10.7(3.2)  Median   10.0   10.5 Range  (7.0, 16.0)  (5.0, 18.0) FiO₂ (%) N21 18 Mean (SD) 61.7 (22.9) 63.9 (20.0) Median   60.0   60.0 Range (1.0, 100.0)  (35.0, 100.0) MAP (cmH₂O) N 21 18 Mean (SD) 19.1 (5.7) 17.0 (3.5)  Median   19.0   17.5 Range (12.0, 32.0) (11.6, 24.0) Set Vt(mL) N 14 11 Mean (SD) 166.1 (154.3) 131.3 (82.9)  Median  108.5  110.0Range  (40.0, 520.0)  (65.0, 366.0) CMV 4 Hours Inspiratory Time (s)(continued) N 21 18 Mean (SD) 0.9 (0.3) 0.8 (0.2) Median   0.8   0.8Range (0.5, 1.5) (0.5, 1.3) HFOV Hertz (min) N  8  7 Mean (SD) 7.1 (1.8)7.4 (1.9) Median   7.5   7.0 Range  (4.4, 10.0)  (4.0, 10.0) MAP (cmH₂O)N  8  7 Mean (SD) 28.3 (5.8)  26.6 (4.7)  Median   27.5   25.0 Range(22.0, 38.0) (21.0, 35.0) Inspiratory Time (s) N  8  7 Mean (SD)  8.5(15.1)  5.0 (12.4) Median   0.3   0.3 Range  (0.0, 33.0)  (0.0, 33.0)FiO₂ (%) N  8  7 Mean (SD) 78.9 (23.5) 52.9 (27.3) Median   84.0   40.0Range  (35.0, 100.0)  (25.0, 100.0) HFOV 4 Hours delta P (cmH₂O)(continued) N  8  6 Mean (SD) 46.9 (14.7) 48.0 (15.5) Median   44.0  45.5 Range (33.0, 81.0) (30.0, 72.0) ABG 4 Hours pH N 28 22 Mean (SD)7.4 (0.1) 7.4 (0.1) Median   7.3   7.4 Range (7.2, 7.6) (7.0, 7.6) PaO₂(mmHg) N 28 22 Mean (SD) 69.5 (26.9) 83.2 (22.6) Median   63.5   78.5Range  (41.0, 177.0)  (57.0, 142.0) SaO₂ (%) N 28 22 Mean (SD) 90.7(6.3)  95.7 (2.9)  Median   92.5   95.9 Range (72.0, 99.5)  (89.0,100.0) PaCO₂ (mmHg) N 28 22 Mean (SD) 50.6 (12.3) 46.0 (18.2) Median  50.8   43.0 Range (27.3, 73.0)  (33.0, 120.7) ABG 4 Hours BE (mEq/L)(continued) N 28 22 Mean (SD) 2.1 (5.7) 0.7 (4.1) Median   2.0   1.0Range (−7.5, 14.0) (−6.0, 7.6)  HCO₃ (mEq/L) N 28 22 Mean (SD) 28.0(5.6)  25.7 (3.9)  Median   27.0   25.8 Range (18.0, 39.0) (19.0, 33.1)12 Hours CMV Rate (/min) N 20 17 Mean (SD) 24.4 (6.6)  24.5 (5.7) Median   24.0   25.0 Range (10.0, 36.0) (15.0, 40.0) Pplat (cmH₂O) N  6 4 Mean (SD) 27.8 (7.2)  25.8 (6.7)  Median   27.5   28.0 Range (20.0,36.0) (16.0, 31.0) PEEP (cmH₂O) N 20 17 Mean (SD) 10.8 (3.6)  10.6(3.2)  Median   10.5   10.0 Range  (5.0, 22.0)  (5.0, 18.0) CMV 12 HoursFiO₂ (%) (continued) N 20 17 Mean (SD) 61.0 (22.2) 59.0 (18.9) Median  55.0   55.0 Range  (21.0, 100.0)  (36.0, 100.0) MAP (cmH₂O) N 20 17Mean (SD) 18.0 (6.1)  16.7 (3.8)  Median   17.0   18.0 Range (11.0,36.0) (10.0, 24.0) Set Vt (mL) N 12 13 Mean (SD) 134.6 (116.5) 126.5(89.2)  Median  101.0  100.0 Range  (25.0, 380.0)  (70.0, 409.0)Inspiratory Time (s) N 20 17 Mean (SD) 0.9 (0.3) 0.8 (0.2) Median   0.8  0.8 Range (0.5, 1.5) (0.5, 1.3) HFOV 12 Hours Hertz (min) N  9  8 Mean(SD) 6.5 (1.8) 7.9 (1.6) Median   6.0   7.5 Range  (4.4, 10.0)  (6.0,10.0) HFOV 12 Hours MAP (cmH₂O) (continued) N  9  8 Mean (SD) 28.7(5.7)  25.5 (5.2)  Median   29.0   23.9 Range (22.0, 39.0) (20.0, 36.0)Inspiratory Time (s) N  9  8 Mean (SD)  7.5 (14.4)  4.4 (11.6) Median  0.3   0.3 Range  (0.0, 33.0)  (0.0, 33.0) FiO₂ (%) N  9  8 Mean (SD)60.3 (23.0) 43.8 (16.0) Median   58.0   42.5 Range  (30.0, 100.0) (25.0,70.0) delta P (cmH₂O) N  9  7 Mean (SD) 48.3 (14.1) 46.1 (14.3) Median  49.0   36.0 Range (33.0, 82.0) (34.0, 69.0) ABG pH N 26 25 Mean (SD)7.4 (0.1) 7.4 (0.1) Median   7.4   7.4 Range (7.1, 7.6) (7.2, 7.5) HFOV12 Hours MAP (cmH₂O) (continued) N  9  8 Mean (SD) 28.7 (5.7)  25.5(5.2)  Median   29.0   23.9 Range (22.0, 39.0) (20.0, 36.0) InspiratoryTime (s) N  9  8 Mean (SD)  7.5 (14.4)  4.4 (11.6) Median   0.3   0.3Range  (0.0, 33.0)  (0.0, 33.0) FiO₂ (%) N  9  8 Mean (SD) 60.3 (23.0)43.8 (16.0) Median   58.0   42.5 Range  (30.0, 100.0) (25.0, 70.0) deltaP (cmH₂O) N  9  7 Mean (SD) 48.3 (14.1) 46.1 (14.3) Median   49.0   36.0Range (33.0, 82.0) (34.0, 69.0) ABG pH N 26 25 Mean (SD) 7.4 (0.1) 7.4(0.1) Median   7.4   7.4 Range (7.1, 7.6) (7.2, 7.5) ABG 12 Hours PaO₂(mmHg) (continued) N 26 25 Mean (SD) 72.1 (27.5) 68.7 (20.9) Median  64.5   68.0 Range  (29.0, 156.0)  (0.8, 118.0) SaO₂ (%) N 26 25 Mean(SD) 90.1 (10.3) 93.1 (3.2)  Median   91.2   94.0 Range (54.0, 99.5)(84.0, 99.0) PaCO₂ (mmHg) N 26 25 Mean (SD) 51.1 (9.5)  47.4 (8.3) Median   50.7   48.4 Range (31.0, 67.0) (33.0, 68.0) BE (mEq/L) N 26 25Mean (SD) 3.1 (5.7)  1.1 (4.1) Median   2.0   2.0 Range (−4.5, 17.0)(−6.5, 8.0)  HCO₂ (mEq/L) N 26 25 Mean (SD) 28.9 (5.7)  26.7 (4.1) Median   28.0   27.0 Range (21.0, 40.0) (18.4, 35.9) 24 Hours CMV Rate(/min) N 19 20 Mean (SD) 23.4 (7.5)  25.0 (6.6)  Median   22.0   25.5Range (10.0, 36.0) (15.0, 40.0) Pplat (cmH₂O) N  7  3 Mean (SD) 29.3(6.0)  30.0 (4.6)  Median   30.0   29.0 Range (21.0, 38.0) (26.0, 35.0)PEEP (cmH₂O) N 19 20 Mean (SD) 10.4 (3.8)  9.8 (2.9) Median   10.0  10.0 Range  (5.0, 22.0)  (5.0, 16.0) FiO₂ (%) N 19 20 Mean (SD) 56.9(20.4) 58.1 (16.6) Median   55.0   55.0 Range  (21.0, 100.0)  (35.0,100.0) MAP (cmH₂O) N 19 20 Mean (SD) 17.2 (5.5)  16.0 (3.9)  Median  15.0   15.5 Range (10.0, 30.0) (10.0, 26.0) CMV 24 Hours Set Vt (mL)(continued) N 13 11 Mean (SD) 126.9 (114.0) 123.3 (86.4)  Median   99.0 100.0 Range  (35.0, 380.0)  (60.0, 370.0) Inspiratory Time (s) N 19 20Mean (SD) 0.9 (0.3) 0.8 (0.2) Median   0.8   0.8 Range (0.5, 1.4) (0.6,1.1) HFOV Hertz (min) N  9  5 Mean (SD) 7.0 (1.9) 8.3 (1.9) Median   7.0  8.0 Range  (4.4, 10.0)  (5.5, 10.0) MAP (cmH₂O) N  9  5 Mean (SD) 26.1(4.1)  25.2 (4.2)  Median   26.0   24.0 Range (21.0, 35.1) (20.9, 32.0)Inspiratory Time (s) N  9  5 Mean (SD)  3.9 (10.9)  6.8 (14.6) Median  0.3   0.3 Range  (0.0, 33.0)  (0.0, 33.0) HFOV 24 Hours FiO₂ (%)(continued) N  9  5 Mean (SD) 54.6 (23.0) 44.0 (20.4) Median   50.0  35.0 Range  (30.0, 100.0) (32.0, 80.0) delta P (cmH₂O) N  9  4 Mean(SD) 48.2 (15.4) 41.3 (12.2) Median   43.0   38.5 Range (29.0, 84.0)(30.0, 58.0) ABG pH N 27 24 Mean (SD) 7.4 (0.1) 7.4 (0.1) Median   7.4  7.4 Range (7.3, 7.5) (7.3, 7.5) PaO₂ (mmHg) N 27 24 Mean (SD) 76.1(23.5) 71.4 (16.8) Median   72.0   69.0 Range  (40.8, 155.9)  (44.7,102.0) SaO₂ (%) N 27 24 Mean (SD) 94.0 (4.5)  92.2 (5.4)  Median   95.9  93.0 Range  (81.0, 100.0) (72.9, 98.0) ABG 24 Hours PaCO₂ (mmHg)(continued) N 27 24 Mean (SD) 52.1 (11.2) 47.2 (11.5) Median   50.6  45.4 Range (34.9, 81.5) (32.4, 85.0) BE (mEq/L) N 27 24 Mean (SD) 4.0(4.7) 2.3 (3.8) Median   2.6   2.8 Range (−2.2, 16.0) (−5.0, 8.0)  HCO₃(mEq/L) N 27 24 Mean (SD) 29.8 (5.6)  30.6 (14.1) Median   29.0   28.0Range (21.9, 45.0) (20.6, 94.0) Extubation Criteria CMV Rate (/min) N 2320 Mean (SD) 14.3 (8.3)  16.3 (7.9)  Median   12.0   15.5 Range  (0.0,36.0)  (0.0, 34.0) Pplat (cmH₂O) N  3  3 Mean (SD) 18.0 (7.2)  21.0(6.2)  Median   20.0   19.0 Range (10.0, 24.0) (16.0, 28.0) CMVExtubation PEEP (cmH₂O) (continued) N 25 21 Mean (SD) 5.8 (0.9) 5.8(0.7) Median   6.0   6.0 Range (4.0, 8.0) (5.0, 8.0) FiO₂ (%) N 25 21Mean (SD) 39.8 (9.1)  38.1 (12.5) Median   40.0   40.0 Range (25.0,60.0)  (0.4, 60.0) MAP (cmH₂O) N 24 20 Mean (SD) 10.5 (3.2)  10.2 (2.3) Median   10.0   10.0 Range  (5.0, 17.0)  (8.0, 18.0) Set Vt (mL) N 17 10Mean (SD) 169.0 (145.3) 106.9 (33.6)  Median  110.0  109.5 Range  (0.0,450.0)  (55.0, 160.0) Inspiratory Time (s) N 20 18 Mean (SD) 0.9 (0.2)0.8 (0.1) Median   0.8   0.8 Range (0.6, 1.6) (0.5, 1.0) ABG pH N 23 15Mean (SD) 7.4 (0.1) 7.4 (0.1) Median   7.4   7.4 Range (7.2, 7.5) (7.3,7.5) PaO₂ (mmHg) N 23 15 Mean (SD) 88.4 (26.2) 91.8 (42.3) Median   83.0  78.0 Range  (46.0, 156.0)  (42.0, 212.0) SaO₂ (%) N 23 15 Mean (SD)95.6 (3.9)  94.6 (5.9)  Median   97.0   96.0 Range  (82.0, 100.0) (76.0, 100.0) PaCO₂ (mmHg) N 23 15 Mean (SD) 45.6 (6.7)  47.5 (8.4) Median   48.0   44.0 Range (30.8, 53.5) (33.5, 64.0) BE (mEq/L) N 23 15Mean (SD) 4.4 (6.7) 5.0 (2.6) Median   2.3   4.0 Range (−6.0, 23.0) (1.0, 11.0) ABG Extubation HCO₃ (mEq/L) (continued) N 23 15 Mean (SD)28.5 (5.4) 30.2 (2.8)  Median   27.5   31.0 Range (20.9, 40.0) (25.4,37.0) Abbreviations: CMV = conventional mechanical ventilation; Pplat =plateau pressure; PEEP = positive end-expiratory pressure; FiO₂ =fraction of inspired oxygen concentration; MAP = mean airway pressure;Vt = tidal volume; HFOV = high-frequency oscillatory ventilation; deltaP = amplitude; ABG = arterial blood gases; PaO₂ = partial pressure ofoxygen; SaO₂ = oxygen saturation (arterial); PaCO₂ = partial pressure ofcarbon dioxide (arterial); BE = base excess; HCO₃ = bicarbonate ion.

Discussion and Overall Conclusions

Subjects who received inhaled nitric oxide were no more likely toexperience AEs than were those who received placebo, with 21 subjects inthe placebo group (72.4%) reporting 93 AEs and 16 subjects in the nitricoxide group (61.5%) reporting 52 AEs. Four AEs, reported by 2 subjectsin the placebo group, were suspected to have a relationship totreatment.

The frequencies of treatment discontinuation due to AEs were 6.9% forthe placebo group and 3.9% for the nitric oxide group. Compared withsubjects treated with placebo, subjects treated with nitric oxidereported fewer serious AEs during the study (27.6% vs. 3.9%) and had ahigher survival rate (72.4% vs. 88.5%). No death, serious AE, severe AE,or AE resulting in treatment discontinuation was suspected to be relatedto study treatment.

Percent methemoglobin levels for subjects who inhaled nitric oxide 5 ppmwere equal to or less than those for subjects in the placebo group atmost time points during the study, indicating that inhaled nitric oxideis well tolerated and is unlikely to be associated with high levels ofmethemoglobin at the low dose used in this study.

The safety profile of inhaled nitric oxide 5 ppm appears to comparefavorably with that of placebo, with regard to methemoglobin levels,frequency of AEs and, particularly, mortality rates. No serious concernsabout the use of inhaled nitric oxide were generated by the results ofthis study, and it appears that inhaled nitric oxide 5 ppm is safe andwell tolerated by children with acute hypoxemic respiratory failure.

What is claimed is:
 1. A method of treating acute respiratory distress syndrome (ARDS) in children comprising administering a gas comprising nitric oxide (NO) to a child in need thereof at a dose in the range from about 2 ppm to about 8 ppm NO for a treatment period of at least 24 hours.
 2. The method of claim 1, wherein NO is administered for a treatment period of at least 2 days.
 3. The method of claim 1, wherein NO is administered for a treatment period of at least 3 days.
 4. The method of claim 1, wherein NO is administered for a treatment period up to 2 months.
 5. The method of claim 1, wherein NO is administered at a dose in the range from about 2 ppm to about 6 ppm NO.
 6. The method of claim 1, wherein NO is administered at a dose of about 5 ppm.
 7. The method of claim 1, wherein administration of NO increases the number of days that the child is alive and ventilator-free at 28 days after the start of NO administration.
 8. The method of claim 1, wherein the child is not subjected to extracorporeal membrane oxygenation during NO administration.
 9. The method of claim 1, wherein the child is less than 17 years old.
 10. The method of claim 1, wherein the child is determined to have a ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO₂/FiO₂ ratio) of less than
 300. 11. A method of treating acute respiratory distress syndrome (ARDS) in children comprising administering a gas comprising nitric oxide (NO) to a child in need thereof at a dose in the range from about 2 ppm to about 6 ppm NO for a treatment period of at least 2 days.
 12. The method of claim 11, wherein NO is administered for a treatment period of at least 3 days.
 13. The method of claim 11, wherein NO is administered for a treatment period up to 2 months.
 14. The method of claim 11, wherein NO is administered at a dose of about 5 ppm.
 15. The method of claim 11, wherein administration of NO increases the number of days that the child is alive and ventilator-free at 28 days after the start of NO administration.
 16. The method of claim 11, wherein the child is not subjected to extracorporeal membrane oxygenation during NO administration.
 17. The method of claim 11, wherein the child is less than 17 years old.
 18. The method of claim 11, wherein the child is determined to have a ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO₂/FiO₂ ratio) of less than
 300. 19. A method of treating acute respiratory distress syndrome (ARDS) in children less than 17 years old, the method comprising administering a gas comprising nitric oxide (NO) to a child in need thereof at a dose of about 5 ppm NO for a treatment period of at least 24 hours.
 20. The method of claim 19, wherein the child is not subjected to extracorporeal membrane oxygenation during NO administration. 